Claus Jorgensen - Systems Oncology

The Tumour Stroma in Pancreatic Cancer

Pancreatic Ductal Adenocarcinoma (PDA) has a dismal prognosis with a medium survival below 6 month and an average 5-year survival below 5%. This is due to the aggressive nature of the cancer, a lack of effective therapy and late diagnosis. The most frequent occurring genetic mutations include activating mutations in the oncogene KRAS and inactivating mutations in the tumour suppressors CDKN2A, TP53 and SMAD4, however these mutations are currently undruggable.

PDAC is characterized by an extensive stromal reaction, which takes up on average ~80% of the tumour volume. The tumour stroma contains cellular and non-cellular elements such as an extensively modified extracellular matrix and infiltrating immune- and fibroblastic cells. While cells in the tumour microenvironment have been shown to promote progression and limit therapeutic efficacy, recent data has demonstrate that stromal cells also may be tumour restrictive. Importantly, while emerging data has demonstrated heterogeneity across the stromal infiltrate, there is little understanding of the functional consequence of such heterogeneity.

The aim to the project is to systematically characterize the impact of stromal elements on tumour cell progression and drug resistance in human PDA. This will include high dimensional single cell analysis across primary tissue by single cell sequencing (scRNAseq) and mass cytometry (CyTOF), isolation of cell populations of interest and interrogation by proteomics, CyTOF and CRISPR screening. This is an exciting and stimulating project that will challenge the current view of tumour-stroma interactions. A major ambition of this project aims to identify and validate specific mechanisms whereby fibroblast plasticity alters tumour cell interactions and ultimately regulates tumour cell therapeutic response. This studentship builds on our extensive experience signalling (Tape et al Cell 2016, Tape et al MCP 2014; Worboys et al Nat Methods 2014; Jorgensen 2009 Science).